Neuroimaging in Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease causing widespread tissue damage in the brain and spinal cord. This disease is the leading cause of non-traumatic neurological disability among young adults. MRI plays a key role in the diagnosis, management and research of MS.

Headed by Professor Hartwig Siebner, the aim of the Neuroimaging in Multiple Sclerosis (NiMS) group is to push the frontiers of MRI to capture MS-related tissue damage and uncover the underlying pathophysiological mechanisms. The group uses a wide range of MR-based techniques such as functional MRI, magnetic resonance spectroscopy (MRS), and diffusion weighted imaging (DWI), but also electrophysiological methods such as electroencephalography (EEG) and transcranial magnetic stimulation (TMS). The current focus is on exploiting the potential of MRI at ultra-high field strength (7 tesla) to detect neocortical involvement and characterize microstructural changes in cerebral white matter.

An image based on diffusion weighted imaging demonstrating fibre directionality in the coronal representation of corpus callosum. Estimating voxelwise fibre directions is the first stage in the process of mapping structural brain connectivity in patients with multiple sclerosis.

Neuroimaging research in the field of MS has a long tradition at DRCMR and greatly benefits from a long-standing and inspiring collaboration with the Danish Multiple Sclerosis Centre, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Denmark. In recent years, the NiMS group pursued several lines of neuroimaging research, including studies of the blood-brain barrier dysfunction in normal appearing white matter (PhD project by Henrik Lund) and the atrophy pattern of the upper cervical spinal cord (Ellen Grade and Henrik Lundell). Together with the DRCMR Reader Centre, the NIMS group participates in the analysis of the MRI data that are acquired at DRCMR as part of investigator-driven as well as company initiated clinical trials.

An overarching theme of our research is to examine how MS alters functional and structural brain connectivity and how such MS-related connectivity changes contribute to clinical disability (Kasper W. Andersen, Kristoffer H. Madsen). Using rs-fMRI, the NiMS group was able to identify distinct changes in functional connectivity in the motor resting-state network in a group of patients with relapsing-remitting or secondary progressive MS (PhD project by Anne-Marie Dogonowski). We found that MS impairs regional functional connectivity in the cerebellum. At the brain network level, patients with MS showed a more widespread coupling of the basal ganglia with the motor resting-state network, indicating an impaired “funneling” function of the basal ganglia in MS. Moreover, resting-state connectivity of pre-motor cortex reflected the degree of disability on the Expanded Disability Status Scale (EDSS).

Key projects

What causes fatigue in patients with multiple sclerosis? – A network perspective

We are currently conducting a comprehensive multi-modal brain mapping study, in which we aim at delineating abnormalities in brain function and structure that lead to fatigue in patients with MS. Fatigue is one of the most common symptoms in Multiple Sclerosis (MS). It has been suggested that fatigue is a consequence of disease-related microstructural alterations in specific white matter (WM) tracts. By applying anatomical connectivity mapping (ACM), we wish to probe whether fatigued MS patients have different levels of anatomical connectedness compared to non-fatigued MS patients. (PhD projects by Olivia Svolgaard and Christian Bauer).

Cortical lesion in primary sensorymotor hand area and their impact on dexterity in multiple sclerosis: a 7T MRI study

In this project, we wish to clarify the impact of regional cortical lesions within the sensorymotor hand area (SM1-HAND) on cortical function and manual dexterity. Exploiting the increased sensitivity of ultra-high field 7 Tesla MRI to detect cortical lesions, we will assess the number, size and regional distribution of cortical lesions in SM1-HAND, and relate regional lesion load in SM1-HAND to MRI-based, electrophysiological, and behavioural correlates of hand function (PhD project by Mads Alexander Just Madsen).

Diffusion weighted magnetic resonance spectroscopy at ultra-high field:
Unravelling microstructural changes in cerebral white matter in patients with multiple sclerosis

We are currently pursuing the first clinical ultra-high field (7T) MR study in Denmark. In this project, we will combine magnetic resonance spectroscopy with diffusion MRI to shed new light into the microstructural alterations in major motor white-matter tract caused by MS. The project is conducted by Senior Researcher Henrik Lundell who received a “Sapere Aude” award by the Danish Council for Independent Research.

Research funding:

We wish to thank the Danish Multiple Sclerosis Society, the Danish Council for Independent Research, Jascha fonden, Torben Fogs og Erik Triers Fond, and Biogen-Idec, Denmark, for their generous support. Christian Bauer´s PhD project was co-financed by Metropolitan University College, Copenhagen, Denmark.

Selected Publications

Madsen MAJ, Wiggermann V, Bramow S, Christensen JR, Sellebjerg F, Siebner HR. 2021. Imaging cortical multiple sclerosis lesions with ultra-high field MRI. NeuroImage. Clinical. 32:1-14. https://doi.org/10.1016/j.nicl.2021.102847

Chow HH, Talbot J, Marstrand L, Lundell H, Roman Siebner H, Bach Søndergaard H, Sellebjerg F. 2021. Smoking, cardiovascular risk factors and LRP2 gene variation: Associations with disease severity, cognitive function and brain structure in primary progressive multiple sclerosis. Multiple Sclerosis and Related Disorders. 56:1-7. https://doi.org/10.1016/j.msard.2021.103296

Ruiu E, Dubbioso R, Madsen KH, Svolgaard O, Raffin E, Andersen KW, Karabanov AN, Siebner HR. 2020. Probing Context-Dependent Modulations of Ipsilateral Premotor-Motor Connectivity in Relapsing-Remitting Multiple Sclerosis. Frontiers in Neurology. 11:1-10. Available from: 10.3389/fneur.2020.00193

Bauer C, Dyrby TB, Sellebjerg F, Madsen KS, Svolgaard O, Blinkenberg M, Siebner HR, Andersen KW. 2020. Motor fatigue is associated with asymmetric connectivity properties of the corticospinal tract in multiple sclerosis. NeuroImage. Clinical. 28:1-12. Available from: 10.1016/j.nicl.2020.102393

Lundell, H., Svolgaard, O., Dogonowski, A-M., Romme Christensen, J., Selleberg, F., Soelberg Sørensen, P., Blinkenberg, M., Siebner, H. R. & Garde, E.
Spinal cord atrophy in anterior-posterior direction reflects impairment in multiple sclerosis.
Acta Neurologica Scandinavica. 136, 4, p. 330-337, 2017.

Schreiber K, Magyari M, Sellebjerg F, Iversen P, Garde E, Gøbel Madsen C, Börnsen L, Christensen JR, Ratzer R, Siebner HR, Laursen B, Soelberg Sorensen P. High-dose erythropoietin in patients with progressive multiple sclerosis: a randomized, placebo controlled, phase 2 trial. Mult Scler 2016: Epub ahead of print.

Dogonowski AM, Blinkenberg M, Paulson OB, Sellebjerg F, Soelberg Sørensen P, Siebner HR, Madsen KH. Recovery from an acute relapse is associated with changes in motor resting-state connectivity in multiple sclerosis. J Neurol Neurosurg Psychiatry 2016;87:912-914.

Ratzer R, Iversen P, Börnsen L, Dyrby T, Romme Christensen J, Ammitzbøll C, Madsen C, Garde E, Lyksborg M, Andersen B, Hyldstrup L, Soelberg Sørensen P, Siebner HR, Sellebjerg F. Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis. Mult Scler 2016;22:926-934.

Voldsgaard A, Bager P, Garde E, Åkeson P, Leffers AM, Kapel C, Roepstorff A, Thamsborg SM, Melbye M, Siebner H, Søndergaard HB, Sellebjerg F, Soelberg Sørensen P. Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect. Mult Scler 2015;21:1723-1729.

Weier K, Banwell B, Cerasa A, Collins DL, Dogonowski AM, Lassmann H, Quattrone A, Sahraian MA, Siebner HR, Sprenger T. The role of the cerebellum in multiple sclerosis. Cerebellum 2015;14:364-374.

Christensen JR, Ratzer R, Börnsen L, Lyksborg M, Garde E, Dyrby TB, Siebner HR, Sorensen PS, Sellebjerg F. Natalizumab in progressive MS: Results of an open-label, phase 2A, proof-of-concept trial. Neurology 2014;82:1499-1507.

Lyksborg M, Siebner HR, Sørensen PS, Blinkenberg M, Parker GJM, Dogonowski A, Garde E, Larsen R, Dyrby TB. Secondary progressive and relapsing remitting multiple sclerosis leads to motor-related decreased anatomical connectivity. PLOS ONE 2014;9, e95540.

Christensen JR, Ratzer R, Börnsen L, Lyksborg M, Garde E, Dyrby TB, Siebner HR, Sørensen PS, Sellebjerg F. Natalizumab in progressive MS – results of an open-label phase 2A proof-of- concept trial. Neurology 2014;82:1499-1507.

Dogonowski, A.-M., Andersen, K. W., Madsen, K. H., Sørensen, P. S., Paulson, O. B., Blinkenberg, M., & Siebner, H. R. Multiple sclerosis impairs regional functional connectivity in the cerebellum. NeuroImage: Clinical, 2014, 4:130–138.